Membrane-Proximal Domain of a Disintegrin and Metalloprotease-17 Represents the Putative Molecular Switch of Its Shedding Activity Operated by Protein-disulfide Isomerase.

Düsterhöft, S., Jung, S., Hung, C. W., Tholey, Andreas, Sönnichsen, Frank, Grötzinger, J. and Lorenzen, I. (2013) Membrane-Proximal Domain of a Disintegrin and Metalloprotease-17 Represents the Putative Molecular Switch of Its Shedding Activity Operated by Protein-disulfide Isomerase. Journal of the American Chemical Society, 135 (15). pp. 5776-5781. DOI 10.1021/ja400340u.

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Abstract

A disintegrin and metalloprotease-17 (ADAM17) is a major sheddase responsible for the regulation of a wide range of biological processes, like cellular differentiation, regeneration, or cancer progression. Hitherto, the mechanism regulating the enzymatic activity of ADAM17 is poorly understood. Recently, protein-disulfide isomerase (PDI) was shown to interact with ADAM17 and to down-regulate its enzymatic activity. Here we demonstrate by NMR spectroscopy and tandem-mass spectrometry that PDI directly interacts with the membrane-proximal domain (MPD), a domain of ADAM17 involved in its dimerization and substrate recognition. PDI catalyzes an isomerization of disulfide bridges within the thioredoxin motif C600XXC603 of the MPD and results in a drastic structural change between an active open state and an inactive closed conformation. This conformational change of the MPD putatively acts as a molecular switch, facilitating a global reorientation of the extracellular domains in ADAM17 and regulating its shedding activity.

Document Type: Article
Additional Information: Times Cited: 2 Duesterhoeft, Stefan Jung, Sascha Hung, Chien-Wen Tholey, Andreas Soennichsen, Frank D. Groetzinger, Joachim Lorenzen, Inken
Research affiliation: Kiel University > Kiel Marine Science
OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
Open Access Journal?: No
DOI etc.: 10.1021/ja400340u
ISSN: 0002-7863
Projects: Future Ocean
Date Deposited: 08 Jul 2014 09:00
Last Modified: 16 Jul 2019 10:07
URI: http://oceanrep.geomar.de/id/eprint/24892

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